Field of the Invention
This invention is directed to estrogen compositions for vaginal administration, as well as to methods of making and administering the same.
Related Background Art
Conventional semi-solid estrogen vaginal preparations comprise a two-phase emulsified system. Such conventional estrogen vaginal preparations have a significant hydrophobic oil or wax component, present either as the external or, more typically, the internal phase of a two-phase emulsified system, where water constitutes the other phase. Given the preferential solubility of estrogen in the hydrophobic phase, its availability for release into epithelial tissue upon vaginal application of such a preparation may be restricted.
Another problem encountered with conventional estrogen preparations for vaginal application is that they can be greasy and/or extremely difficult to remove completely from an applicator, particularly if the applicator is washed with water only.
The significant hydrophobic oil or wax component of conventional estrogen vaginal preparations contributes to both of these problems. Pharmaceutical gel compositions containing estrogen may be advantageous for vaginal use. As used herein, the term “gel” is understood to be a semi-solid matrix of particles interpenetrated by a liquid, in which the structural coherent matrix contains a high portion of liquid, usually an aqueous solvent such as water. Such gels comprise a single phase. As used herein, the term “semi-solid” is understood to refer to the rheological properties of the compositions themselves, such that the compositions will flow under an applied force but will remain in situ following application to the vaginal epithelial surface.
The inventors are not aware of any commercially available pharmaceutical gel compositions containing estrogen for vaginal administration. Known pharmaceutical gel compositions for topical administration conventionally comprise polymers, for example, modified cellulose ethers, natural gums or polymers containing pendant carboxylic acid groups, or their esters, or having pendant anhydrides of dicarboxylic acid groups, or mixtures thereof. Carboxylic acid polymers in aqueous systems are conventionally neutralized from a starting pH of about 2.5 to 3.5 to a pH of 4.0 or more in order to achieve gelation. Conventional neutralizers comprise sodium hydroxide, potassium hydroxide, ammonium hydroxide, arginine, aminomethyl propanol, tetrahydroxypropyl ethylenediamine, triethanolamine, tromethamine, PEG-15 cocamine, diisopropanolamine or triisopropanolamine. However, all polymer gel compositions, exemplified by the foregoing, will require the presence of an estrogen solubilizing agent to substantially solubilize the estrogen. For this reason, known pharmaceutical gel compositions for topical administration may conventionally contain an alcoholic component, ethanol, as an estrogen solubilizer.
More specifically, known pharmaceutical gel compositions for topical, but not for vaginal, application comprise Estrogel® (Solvay, US) and Sandrena® (Organon, Netherlands). Estrogel® is a hydro-ethanolic gel containing 0.06% estradiol; the excipients are ethanol, Carbomer 934 and triethanolamine, the balance being purified water. Sandrena® is another hydro-alcoholic gel containing 0.1% estradiol; its excipients are Carbomer 934, sodium hydroxide, propylene glycol, ethanol and water. Clearly, the base of these pharmaceutical gel compositions is a mixture of water and ethanol. The ethanol is intended to increase estrogen solubility in the gel and assist absorption into the stratum corneum. While the presence of ethanol may be useful in topical or skin formulations, its presence is counter-productive in mucosal utilities such as vaginal compositions since it is an irritant and it may also have a drying effect.
EP-B-435200 in the names of Nitto Denko Corp. and Teikoku Hormone Mfg. Co. relates to an estrogen-containing gel for topical, but not for vaginal, administration. The gels are covalently crosslinked using, for example, a titanium or aluminum chelate compound. There is no disclosure or suggestion that a gelation promoter might be selected to both solubilize the estrogen and to gel the polymer.
EP-B-813412 in the name of Laboratoire Innothera relates to vaginal gels containing estradiol in a gel containing a polymer that has been gelled by neutralization by a conventional neutralizer. There is no disclosure or suggestion that a gelation promoter might be selected to both solubilize the estrogen and to gel the polymer in a non-aqueous or substantially non-aqueous environment.
DE-A-199 45 522 in the name of Hexal AG relates to compositions for topical administration. The compositions are oil-in-water emulsions containing a polymer as a thickening agent. The compositions are erroneously described in DE-A-1 99 45 522 as gels. There is no disclosure or suggestion that a gelation promoter might be selected to both solubilize the estrogen and to gel the polymer.
Accordingly, pharmaceutical gel compositions containing estrogen for vaginal administration which do not suffer from the deficiencies of conventional vaginal preparations and topical gel compositions are highly desirable.